MXPA02004911A - New use and novel n azabicyclo amide derivatives. - Google Patents

New use and novel n azabicyclo amide derivatives.

Info

Publication number
MXPA02004911A
MXPA02004911A MXPA02004911A MXPA02004911A MXPA02004911A MX PA02004911 A MXPA02004911 A MX PA02004911A MX PA02004911 A MXPA02004911 A MX PA02004911A MX PA02004911 A MXPA02004911 A MX PA02004911A MX PA02004911 A MXPA02004911 A MX PA02004911A
Authority
MX
Mexico
Prior art keywords
oct
azabicyclo
propenamide
phenylpropenamide
disease
Prior art date
Application number
MXPA02004911A
Other languages
Spanish (es)
Inventor
Balestra Michael
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of MXPA02004911A publication Critical patent/MXPA02004911A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Abstract

This invention relates to new use of a compound of general formula (I) wherein: A represents (II), (III), (IV), (V), (VI); D represents oxygen, or sulfur; R1 represents hydrogen or methyl; R2 represents hydrogen, or C1 C4 alkyl; and R3 represents (A), (B), (C), or an enantiomer thereof, and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.

Description

NEW USE AND NEW DERIVATIVES OF N-AZABICICLO-AMIDA Technical Field This invention relates to the new medical use of quinuclidine acrylamides or pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing them. The present invention also relates to certain novel quinuclidine acrylamides or pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing them. In particular, the invention relates to the use of quinuclidine acrylamides for the preparation of medicaments for the treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration, as well as in the treatment and / or prophylaxis of human conditions or conditions in which the Activation of the nicotinic receptor a7 is beneficial.
BACKGROUND OF THE INVENTION The use of compounds which bind to nicotinic acetylcholine receptors in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, REF 138424 attention or cognitive disorders, anxiety, depression, cessation of smoking, neuroprotection, schizophrenia, analgesia, Tourette's syndrome and Parkinson's disease, have been discussed in McDonald et al. (1995) "Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology" ("Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology") / Chapter 5 in Annual Reports in Medicinal Chemistry, vol 30, pp. 41-50, Academic Press Inc. San Diego, CA, and in Williams et al. (1994) "Neuronal Nicotin Acetylcholine Receptors" ("Neuronal Nicotinic Acetylcholine Receptors"), Drugs News &Perspectives , vol.7, pp. 205-223 The use of certain quinuclidine acrylamide derivatives, for which the present invention has found a new pharmacological use, is known from EP 581165-A2 for having an antitussive effect. of the compounds was described as being "without effects on the central nervous system", and the use of compounds for the treatment of conditions involving the central nervous system was not suggested.
Description of the Invention In accordance with the present invention it has been found that the compounds of the general formula I: where A represents: D represents oxygen, or sulfur; R1 represents hydrogen or methyl; R 2 represents hydrogen, or C 1 -C 4 alkyl; R represents: R4, R5 and R6 are independently hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -C02R7, -CN, -CF3, or Ar, provided that at least one of R4 and R5 represent Ar; Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, or a fused heteroaromatic or aromatic ring system of 8, 9 or 10 elements containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may be optionally substituted with one or more substituents selected from the following: hydrogen, halogen, C 1 -C 4 alkyl, C2-C4 alkenyl, C2-C alkynyl, aryl, heteroaryl, -C0R7, -CN, -N02, -NRRR9, -CF3, -OR? n; R8, R9, and R10 are independently hydrogen, C1-C4 alkyl / aryl, heteroaryl, -C (O) R -CiO NHR 112 -C (0) R13, -S02R14 or R8 and R9 can together be (CH2) 3Q (CH2) k where Q is O, S, NR 15, or a bond j is 2 to 4; k is 0 to 2; R7, R10, R11, R12, R13, R14 and R15 are independently C? -C alkyl, aryl, or heteroaryl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof, are employed for the preparation of a medicament for the treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration. Examples of such conditions, conditions or disorders are Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficit, memory loss, Hyperactivity Disorder of Deficiency of Attention, anxiety, schizophrenia, mania or manic depression, Dementia Lewy Body, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is cholinergic synapse loss, jetlag, cessation of smoking, nicotinic addition including the one that results from exposure to products that contain nicotine, pain, and ulcerative colitis. Unless otherwise indicated, the C? -C alkyl groups, referred to herein, for example methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, either alone or part of other groups, they can be straight or branched chain, and the C3-C4 alkyl groups can also be cyclic, for example cyclopropyl, cyclobutyl. Unless indicated otherwise, aryl refers to a phenyl ring which may be optionally substituted with one of the following substituents selected from the following: halogen, Ci-C4 alkyl, C2-C4 alkenyl, C2 alkynyl -C4, -C02R7, -CN, -N02, -NR8R9, -CF3, -OR10. Unless otherwise indicated, heteroaryl refers to a heteroaromatic or aromatic ring of 5 or 6 elements containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, with the proviso that the ring contains at least one nitrogen, oxygen, or sulfur atom, which may be optionally substituted with one or more substituents selected from the following: C?-C4 alkyl / C2-C4 alkenyl, C2-C4 alkynyl, -C02R7, -CN, -N02, -NR8R9, -CF3, -OR10. Unless otherwise indicated, halogen refers to fluoro, chloro, bromo or iodo. Pharmaceutically acceptable derivatives include solvates and salts. For example, the compounds of the formula I can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example, meleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic acids, tartaric and methanesulfonic. Preferred embodiments of the invention include compounds of formula I, wherein A represents: II or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein D represents oxygen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of formula I, wherein R 2 represents hydrogen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein R3 represents: or an enantiomer thereof, and pharmaceutically salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein R3 represents: when R4 represents Ar; R5 represents hydrogen, or C? -C4 alkyl; R6 represents hydrogen, or halogen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments also include compounds of formula I, wherein A represents: II D represents oxygen; R represents hydrogen; R represents: or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein A represents: II D represents oxygen; R2 represents hydrogen; R represents: R represents Ar; R represents hydrogen, or C 1 -C 4 alkyl; R6 represents hydrogen, or halogen; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one nitrogen atom. sulfur, or a fused heteroaromatic or aromatic ring system of 8, 9 or 10 elements containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may be optionally substituted with one or more of the substituents selected from the following: hydrogen, halogen, C? -C4 alkyl / C2-C4 alkenyl, CC alkynyl, aryl, heteroaryl, -C02R7, -CN, -N02, -NR8R9, -CF3, -OR10; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred embodiments of the invention also include compounds of the formula I, wherein A represents: D represents oxygen; R1 and R2 are hydrogen; R3 represents: or R represents: wherein: R4 represents Ar; R 5 represents hydrogen or C 1 -C 4 alkyl; R6 represents hydrogen or halogen; Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing from zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, including phenyl, 2-, 3- or 4-pyridyl , 2- or 3-furanyl, and 2- or 3-thienyl, any of which may be optionally substituted with one or more substituents selected from the following: hydrogen, halogen, C 1 -C alkyl, C 1 -C 4 alkenyl, C2-C4 alkynyl, -C02R7, -CN, -N02, -NR8R9, -CF3, -OR10; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Preferred compounds of the formula I include the following: N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropionamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-nitrophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-nitrophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-aminophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [Z -3- (2-methoxyphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) -N-methyl- (E-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [.E-2-phenylcyclopropanecarboxamide); N- (1-Azabicyclo [2.2.2] oct-3-yl). { Z-2-fluoro-3-phenylpropene ida); N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-fomamidophenyl) propenamide]; N- (1-Azabicyclo [2 .2.2] oct-3-yl) [-3- (4-nitrophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) (E-3- (4-aminophenyl) propenamide; N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -3- (4-formamidophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) (2-3-methyl-3-phenylpropenamide); N- (l-Azabicyclic [2.2. 2] oct-3-yl) [E-3- (4-N-methylaminophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-N, N-dimethylaminophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) (Z-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) (7 -7-methyl-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl). { E-2, 3-diphenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-methoxyphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-methyl-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-ethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-ethoxy phenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-fluorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-fluorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E- (2-chlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-chlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-chlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) - [E-3- (3,4-dichlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) - [E-3- (3-bromophenyl) propenamide]; ? - (1-Azabicyclo [2.2.2] oct-3-yl) - [E-3- (4-bromophenyl) ropenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-iodophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-iodophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-trifluoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) - [1 -3- (3-trifluoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-thienyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-thienyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (5-nitro-2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (5-methoxy-3-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (5-hydroxy-3-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; N- (endo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide); N- (exo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (E-3-phenylpropenamide); or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula I include the following: (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); (5) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropinamide); (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropinamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ 7-3- (2-nitrophenyl) propenamide]; (i 5 5) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [--3- (2-nitrophenyl) propenamide]; (i 5 5) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [--3- (2-aminophenyl) propenamide]; () -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-aminophenyl) propenamide]; (i?) - N- (l-Azabicyclo [2.2.2] oct-3-yl) [2-3- (2-methoxyphenyl) propenamide]; (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) -N-methyl- (3-phenylpropenamide); (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide); (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (2-2-fluoro-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) [-3- (2-formamidophenyl) propenamide]; (i?) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-nitrophenyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3- (4-aminophenyl) propenamide; (R) -N- (1-Azabicyclo [2.2.2] oct- 3-yl) (£ -3- (4-formamidophenyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (.Z-3-methyl-3-phenylpropenamide); (i?) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-N-methylaminophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2 .2] oct-3-yl) [-3- (4-N, N-di-ethylaminophenyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (? t-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-methyl-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -2,3-diphenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3- (4-methoxyphenyl) ropenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct -3-yl) (2-methyl-3-phenylpropenamide); (5) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-methyl-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-ethylphenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct -3-yl) [-3- (2-methylphenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-methoxyphenyl) propenamide ]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (3-methoxyphenyl) propenamide]; (R5) -N- (l-Azabicyclo [2.2.2] ] oct-3-yl) [-3- (4-ethoxyphenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-fluorophenyl) ) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (3-fluorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2 .2] oct-3-yl) [-3- (4-fluorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-chlorophenyl) propenamide]; • (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-chlorophenyl) ropenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-chlorophenyl) ropenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-chlorophenyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3,4-dichlorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3-bromophenyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) - [-3- (4-bro-ofenyl) propenamide]; (R5) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-iodophenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-iodophenyl) propenamide]; (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-trifluoromethylphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [[3- (3- trifluoromethylphenyl) propenamide]]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-pyridyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) ropenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-methoxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-i idazolyl) propenamide]; N- (endo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide); N- (exo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide), or an enantiomer thereof, and pharmaceutically acceptable salts thereof. In another aspect of the present invention, new compounds are provided according to formula I, with the additional proviso that Ar does not represent 2-, 3-, 4-pyridyl, unsubstituted phenyl or phenyl substituted with one or more substituents selected from alkyl C? -C4, C? -C4 alkoxy, halogen, phenoxy, hydroxy, OCOR11,? H2,? HCOR11, and nitro, when: A represents: p VI R represents D represents oxygen; R represents methyl; R2 and R5 both represent hydrogen; R6 represents any of hydrogen, C? -C4 alkyl, phenyl, or cyano; or an enantiomer thereof, and pharmaceutically acceptable salts thereof, which are potent ligands for nicotinic acetylcholine receptors. In a preferred embodiment of this aspect of the invention, there is provided a compound according to formula I, as defined above, wherein A represents: II or an enantiomer thereof, and pharmaceutically acceptable salts thereof. In another preferred embodiment of this aspect of the invention, there is provided a compound according to formula I, as defined above, wherein A represents: II and R6 represents any of 2-furyl 3-furyl; 2-thienyl; 3-thienyl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. Among these compounds, the following compounds are preferred: N- (l-Azabicyclo [2.2.2] oct-3-yl) [E3- (3-tri luoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; N- (l-Aza-3-cyanobicyclo [2.2.2] oct-3-yl) [-3-phenylpropenamide]; N- (l-Aza-3-methylbicyclo [2.2.2] oct-3-yl) [E-3-phenylpropenamide]; N- (1-α-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-methoxy-3-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; or an enantiomer and / or pharmaceutically acceptable salts thereof. Among these compounds, the following compounds are particularly preferred: (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-trifluoromethylphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) ropenamide]; (R) -N- (1-Azabicyclic [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; N- (l-Aza-3-cyanobicyclo [2.2.2] oct-3-yl) [-3-phenylpropenamide]; N- (l-Aza-3-methylbicyclo [2.2.2] oct-3-yl) [E-3-phenylpropenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (5-methoxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; Pharmaceutically acceptable derivatives include solvates and salts. For example, the compounds of the formula I can form acids with acid addition salts, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic acids. , tartaric and methanesulfonic. The compounds of the invention have the advantage that they can be less toxic, be more effective, be long acting, have a broader range of activity, be more potent, produce few side effects, are more easily absorbed or have other useful pharmacological properties. .
Methods of Preparation In the reaction schemes and text below, A, R1, R2 and R3, unless otherwise indicated, are as defined above by formula I. The compounds of formula I can be prepared in accordance with the methods summarized in scheme 1.
Scheme 1. The compounds of formula I wherein D represents oxygen can be prepared from compounds of formula VII by reaction with a compound of formula VIII, wherein Y represents a suitable leaving group, using a suitable acylation process. Suitable leaving groups Y include: OH, halogen, OA1-alkyl, O-Aryl, OCQ-Alkyl, OCO-Aryl, azide. A suitable acylation procedure involves treating a compound of formula I with a compound of formula VIII of 0-120 ° C in a suitable solvent. The presence of a base, or when, Y = OH, a coupling agent may also be necessary for the reaction to occur. Suitable bases for the reaction include: 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. The preferred base is N, N-diisopropylethylamine. Suitable coupling agents when Y = OH include: carbodiimides, for example 1,3-dicyclohexylcarbodiimide or l- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphonium reagents, for example benzotriazol-1-yloxytrishexafluorophosphate (dimethylamino) phosphonium or benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate, and uronium reagents, for example O-benzotriazol-1-yl-N, N, Nf, N'-tetramethyluronium tetrafluoroborate The preferred coupling agent is O-benzotriazole tetrafluoroborate -1-il-N, NN ', N'-tetramethyluronium Suitable solvents for the reaction include N, N-dimethylformamide, dimethisulfoxide, tetrahydrofuran, or chloroform The preferred solvent is N, N-di-ethylformamide The reaction was preferably carried out at a temperature of 0-50 ° C, and more preferably at a temperature of 20-30 ° C. Compounds of the formula I wherein D represents oxygen and R 2 represents hydrogen may alternatively be prepared from of the formula IX by treatment with a nitrile of formula X in a suitable solvent in the presence of a suitable acid. Suitable acids include sulfuric acid and suitable solvents include acetic acid. The reaction is carried out at a temperature of 0-50 ° C, and preferably at a temperature of 0-25 ° C. The compounds of the formula I in which D represents sulfur can be prepared from compounds of the formula I in which D represents oxygen by reaction with a suitable sulfide in a suitable solvent. Preferred sulfides are phosphorus sulphides, in particular 4-methoxyphenylthiophosphine sulfide dimer ("Lawesson's Reagent"), and diphosphorus pentasulfide. Suitable solvents for the reaction include aryl hydrocarbon solvents, for example toluene or xylene. The reaction was carried out at a temperature of 0-200 ° C, and preferably at a temperature of 50-180 ° C.
The compounds of the formula VII in which R "represents an aryl group can be prepared from compounds of the formula VII in which R.sub.2 represents hydrogen by a suitable alkylation process.The typical alkylation procedures include treatment with an appropriate alkyl halide or sulfonate ester - and base, for example sodium hydride, in a suitable solvent, for example DMF, or reductive alkylation using the appropriate ketone or aldehyde together with a suitable reducing agent in an inert solvent - the preferred method in a reductive alkylation. Reduction agents include sodium borohydride and sodium cyanoborohydride The preferred reducing agent is sodium borohydride Suitable inert solvents include water, methanol or ethanol The preferred solvent is methanol The reaction is usually conducted at a temperature of 0. -100 ° C, preferably at 20 ° C-65 ° C. Compounds of formula VII are commercially available or they can be prepared by methods known to a person skilled in the art. For example, certain compounds of formula VII can be prepared from compounds of formula IX via a Ritter reaction with a suitable nitrile, followed by hydrolysis of a resulting amide. The compounds of formula VII and X are commercially available or can be prepared by methods known to a person skilled in the art. See, for example, the methods cited in "Comprehensive Organic Transformations" by R.C. Larock (VCH Publishers, 1989), pages 819-995, and the general references cited on page 823 of the same text. It will be appreciated by a person skilled in the art that certain optional aromatic substituents in the compounds of the invention may be introduced using aromatic substitution reactions, or transformations of functional groups to modify an existing substituent, or a combination thereof. Such reactions can be carried out either before or immediately following the processes mentioned above, and are included as part of the aspect of the processes of the invention. Reagents and conditions for such procedures are known in the art. Specific examples of methods which may be employed include, but are not limited to, electrophilic functionalization of an aromatic ring, for example via nitration, halogenation, or acylation; transformation of a nitro group to an amino group, for example via reduction, such as by catalytic hydrogenation; acylation, alkylation or sulfonylation of an amino or hydroxyl group; the replacement of an amino group by another functional group via conversion to an intermediate diazonium salt followed by substitution of the free or nucleophilic radical of the diazonium salt; or the replacement of a halogen by another functional group for example via catalyzed or nucleophilic substitution reactions. Where necessary, hydroxy, amino or other reactive groups can be protected using a protecting group as described in the standard text "Protecting groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts. The reactions described above, unless otherwise indicated, are usually conducted at a pressure of about one to about three atmospheres, preferably at an ambient pressure (about one atmosphere). Unless stated otherwise, the reactions described above are conducted under an inert atmosphere, preferably under a nitrogen atmosphere. The compounds of the invention and intermediates can be isolated from their reaction mixtures by declared techniques. The acid addition salts of the compounds of the formula I which may be mentioned include salts of mineral acids, for example the hydrobromide and hydrochloride salts; and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate, and fumarate salts. The acid addition salts of the compounds of the formula I can be formed by reacting the free base or a salt, enantiomers or protected derivatives thereof, with one or more equivalents of the appropriate acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble or a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which can be removed in vacuum or by freeze drying. The reaction can be a metathetic process or it can be carried out in an ion exchange resin. The compounds of formula I exist in tautomeric or enantiomeric forms, all of which are included within the scope of the invention. The various varied optical isomers can be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallization, or chiral HPLC. Alternatively the individual enantiomers can be worked up by reaction of the appropriate optically active initiator materials, under reaction conditions which do not cause racemization.
Pharmaceutical Compositions A further aspect of the invention relates to a pharmaceutical composition for the treatment or prevention of a condition or disorder as exemplified below arising from the dysfunction of the nicotinic acetylcholine receptor neurotransmitter in a mammal, preferably a human, comprising a The amount of a compound of the formula I, an enantiomer thereof or a pharmaceutically acceptable salt thereof, effective in the treatment or prevention such as a disorder or condition and a pharmaceutically acceptable inert diluent or carrier. A condition or disorder arising from the dysfunction of the nicotinic acetylcholine receptor neurotransmitter in a mammal, preferably a human, can be psychotic disorders or disorders of intellectual deterioration or conditions or conditions in w activation of the nicotinic receptor a7 is beneficial. Examples of such conditions, conditions or disorders include Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Dementia Lewy Body, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in w there is cholinergic synapse loss, jetlag, cessation of smoking, nicotinic addition including that resulting from exposure to nicotine-containing products, pain, and for ulcerative colitis. For the aforementioned uses the administered dosage may, of course, vary with the compounds employed, the mode of administration and the desired treatment. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of about 0.1 mg to about 20 mg per Kg of the animal's body weight, preferably given in divided doses of 1 to 4. times a day or in the form of sustained release. For man, the total daily dose is in the range of up to 5 mg to 1400 mg, more preferably 10 mg to 100 mg and unit dosage forms suitable for oral administration comprising from 2 mg to 1400 mg of the compound administered with a liquid or solid pharmaceutical carrier or diluent.
The compounds of the formula I, or an enantiomer thereof, and pharmaceutically acceptable salts thereof, may be used in their own form or in the form of medicinal preparations suitable for parenteral or enteral administration. According to a further aspect of the invention, there is provided a pharmaceutical composition that preferably includes less than 80% and more preferably less than 50% by weight of a compound of the invention mixed with an inert pharmaceutically acceptable diluent or carrier. Examples of diluents or carriers are: for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; - for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: hardened or natural oils or waxes. Processes for the preparation of such pharmaceutical compositions are also provided, w comprise mixing the ingredients.
Utility An aspect of the invention is the use of a compound according to the invention, an enantiomer thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of one of the conditions or conditions mentioned below.; and a method of treatment or prophylaxis of one of the aforementioned conditions or conditions, w comprise the administration of a therapeutically effective amount of a compound according to the invention, or an enantiomer thereof or a pharmaceutically acceptable salt thereof, to a patient. The compounds to be used according to the invention are nicotinic acetylcholine receptor agonists. While not limited by theory, it was believed that agonists of the nAChR a7 subtype (nicotinic acetylcholine receptor) should be used in the treatment or prophylaxis of psychotic disorders and intellectual deterioration disorders, and have advantages over compounds which are or are also agonists of the nAChR 0C7 subtype. Therefore, the compounds which are selective for the nAChR subtype a? . The use of compounds of the invention is indicated as a pharmaceutical, in particular in the treatment or prophylaxis of psychotic disorders and disorders of intellectual deterioration. Examples of psychotic disorders include schizophrenia, mania or manic depression, and anxiety. Examples of intellectual impairment disorders include Alzheimer's disease, Lewy Body Dementia, learning deficiency, cognitive deficiency, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder. The compounds of the invention can also be used as analgesics in the treatment of pain (including chronic pain) and in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome and neurodegenerative disorders in which there is synapse loss. cholinergic The compounds may also be indicated for the treatment or prophylaxis of jetlag, for use in the induction of smoking cessation, and for the treatment or prophylaxis of nicotinic addition (including that resulting from exposure to products containing nicotine). . It was also believed that the compounds according to the invention are used in the treatment and prophylaxis of ulcerative colitis.
Pharmacology The pharmacological activity of the compounds of the invention can be measured in the tests set forth below: Test A - Assay for affinity to subtype nAChR a7 Link of 1251- -Bungarotoxin to membranes of rat hippocampi. Rat hypocapsules were homogenized in 20 volumes of cold homogenization buffer (HB: concentrations of constituents (mM): tris (hydroxymethyl) aminomethane 50, MgCl2 1, NaCl 120, KCl 5: pH 7.4). The homogenate was centrifuged for 5 minutes at 100 g, the supernatant was saved and the pellet was extracted again. The poured supernatants were centrifuged for 20 minutes at 12000 g, washed and resuspended in HB. Membranes (30-80 μg) were incubated with 5 nM [125I] a-BTX, 1 mg / mL BSA (bovine serum albumin), drug test, and either 2 mM CaCl2 or 0.5 mM EGTA [ethylene glycol] -bis (ß-aminoethyl ether)] for 2 hours at 21 ° C, and then filtered and washed 4 times on Whatman glass fiber filters (thickness C) using a Brandel cell harvester. Filter pretreatment for 3 hours with 1% of (BSA / 0.01% PEI (polyethyleneimine) in water was critical for low filter targets (0.07% of total count per minute.) Non-specific links per 100 μM are described ( -) - nicotine, and the specific binding was typically 75%.
Test B - Assay for affinity to sub-type nAChR a4 Link [3H] - (-) -nicotine. Using a modified procedure by Martino-Barrows and Kellar (Mol Pharm (1987) 31: 169-174), the rat brain (cortex and hippocampus) was homogenized as in the [125I] a-BTX binding assay, centrifuged for 20 minutes at 12,000 xg, washed twice, and then resuspended in HB containing 100 μM of diisopropyl fluorophosphate. After 20 minutes at 4 ° C, membranes (approximately 0.5 mg) were incubated with 3 nM of [3 H] - (-) - nicotine, test drug, 1 μM atropine, and either 2 mM CaCl 2 or 0.5 mM EGTA for 1 hour at 4 ° C, and then filtered on Whatman glass fiber filters (thickness C) (pretreated for 1 hour with 0.5% PEI) using a Brandel cell harvester. Non-specific bonds were described per 100 μM of mineral carbon, and the specific bonds were typically 84%.
Link date analysis for Tests A and B IC50 values and pseudo Hill coefficients (nH) were calculated using the ALLFIT nonlinear curve fixation program (DeLean A, Munson P J and Rodbard D (1977) Am. J.
Physiol., 235: E97-E102). Saturation curves were set to a site model, using the non-linear regression program ENZFITTER (Leatherbarrow, R.J. (1987)), providing KD values of 1.67 and 1.70 nM for the 125I-a-BTX ligands and [3 H] - (-) - nicotine respectively. Ki values were estimated using the Cheng-Prusoff general equation: ((2+ ([ligand] / [KD]) n) i n-l) where a value of n = 1 was used whenever nH < 1.5 and a value of n = 2 is used when nH = 1.5. The samples were subjected to triplicate tests and were typically ± 5%.
The K i values were determined using 6 or more drug concentrations. The compounds of the invention are compounds with binding affinities (Ki) of less than 10 μM in either Test A or Test B, indicating that they are expected to have useful therapeutic activity. The use of compounds of the invention has the advantage that they can be less toxic, be more effective, be long acting, have a broader range of activity, be more potent, produce few side effects, are more easily absorbed or have other properties. useful pharmacological General Experimental Procedures Commercial reagents were used without further purification. The mass spectrum was recorded using either a Hewlett Packard 5988A Mass Spectrometer or a Quattro-1 MicroMass and is reported as m / z for the original molecular ion. The ambient temperature refers to 20-25 ° C.
Examples The following examples are preferred non-limiting examples that include preferred aspects of the invention.
Example 1 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide) (R) -1- Azabicyclo [2.2.2] oct-3- dihydrochloride were combined ilamine (7.5 g, 0.038 mol) and E-3-phenylpropenoic acid (5.6 g, 0.038 mol) in anhydrous N, N-dimethylformamide (570 mL) under nitrogen atmosphere. The resulting mixture was stirred while adding 1-hydroxybenzotriazole monohydrate (5.8 g, 0.0378 moles) of 0-benzotriazol-1-yl-N, N, N'r rN'-tetramethyluronium tetrafluoroborate (12.1 g, 0.038 moles) and added N, N-diisopropylethylamine (26.4 mL). The solution was stirred at room temperature for 6 hours and then placed in a freezer overnight. The solution was concentrated in vacuo and the residue was taken up in chloroform (360 mL) and washed with aqueous sodium hydroxide (1 M, 360 L). The basic layer was extracted twice more with chloroform and the organic layers were combined, dried (MgSO4), and concentrated in vacuo. The compound was then purified on a flash silica gel column with a gradient of methanol / chloroform / 5-20% ammonium hydroxide. The hydrochloride salt was prepared from isopropanol and ethyl acetate, giving 9.5 g of slightly whitish powder; MS (ES +) 257 (MH +).
Example 2 (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide) Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (S) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3-phenylpropenoic acid: MS (ES +) 257 (MH +).
Example 3 (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide) Prepared as free base by a method analogous to that described in Example 1 from dihydrochloride of (RS) -l-azabicyclo [2.2.2] oct-3-ylamine and £ -3-phenylpropenoic acid: MS (ES +) 257 (MH +).
Example 4 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropenamide) Prepared as a free base by a method analogous to that described in Example 1 of (R) dihydrochloride -1-azabicyclo [2.2.2] oct-3-ylamine and 3-phenylpropinoic acid: MS (ES +) 255 (MH +).
Example 5 (5) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropinamide) Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of ( S) -1-azabicyclo [2.2.2] oct-3-ylamine and 3-phenylpropinoic acid: MS (ES +) 255 (MHT).
Example 6 (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) (-3- (2-nitrophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (i) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-nitrophenyl) propenoic acid: MS (ES +) 302 (MH +).
Example 7 (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl [-3- (2-nitrophenyl) -propenamide] Prepared as a free base by a method analogous to that described in the Example 1 from dihydrochloride (S) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (2-nitrophenyl) propenoic acid as a solid: MS (ES +) 302 (MH +).
Example 8 (RS) -N- (1-azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (RS) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (2-nitrophenyl) propenoic acid as a solid: MS (ES +) 302 (MH +).
Example 9 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-aminophenyl) -propenamide] (RS) -N- (l-Azabicyclo [2.2.2 ] oct-3-yl) [£ -3- (2-nitrophenyl) propenamide] (0.42 g, 0.014 mole) prepared was suspended in acetone (4.2 mL) and ammonium chloride was added (0.15 g, 0.028 moles) in water (2.1 mL). The clear solution was refluxed using an oil bath, and then removed from heating while zinc powder was added. (0.42 g, 0.063 moles). The reaction was refluxed for one hour, at which point the conversion was completed by thin layer chromatography. The suspension was diluted with chloroform and saturated sodium bicarbonate, and decanted from the solid zinc. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined layers were dried (MgSO4) and evaporated. The maleate salt was prepared in isopropanol. The solvent was decanted and the orange deliquescent solid was transferred with methanol and removed to give a foamy orange crystal: MS (ES +) 272 (MX).
Example 10 (R) -N- (l-Azabicyclo [2. 2. 2] oct-3-yl) [E-3- (2-aminophenyl) -propenamide] Prepared by a method analogous to that described in Example 9 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) propenamine]: MS (ES +) 272 (MH +).
Example 11 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [Z-3- (2-methoxyphenyl) propenamide Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and Z-3- (2-methoxyphenyl) propenoic acid: MS (ES +) 287 (MH +).
Example 12 (RS) -N- (1-Azabicyclo [2 .2.2] oct-3-yl) -N-methyl- (3-phenylpropenamide) was suspended (RS) -N- (1-azabicyclo [2.2. 2] oct-3-yl) (E-3-phenylpropenamide) (0.15 g, 0.059 mol) in anhydrous tetrahydrofuran under nitrogen atmosphere. The reaction mixture was cooled with an ice bath while drier 1.0 was added by borane / tetrahydrofuran commercial complex (0.59 mL). The suspension dissolved immediately and the solution was stirred at 0 ° C for one hour. The reaction was carefully cooled rapidly by addition of water (2 mL) with cooling. The reaction was then diluted with brine and methanol chloride. The layers were separated and the aqueous layer was extracted twice more with methylene chloride. The combined organic layers were dried (MgSO4) and evaporated in vacuo. Sodium hydride (28 mg, 0.00071 mol) was suspended in anhydrous N, N-di-ethylformamide (2 mL) under nitrogen. The crude borane complex was dissolved in N-N-dimethylformamide (1 mL) and added dropwise. The reaction was stirred at room temperature for 30 minutes and then methyl iodide (55 μL, 0.000885 moles) was added by syringe. After stirring for 2 hours the reaction was cooled with an ice bath and quenched with water (1 mL). The suspension was diluted with saturated sodium bicarbonate and ethyl acetate and the layers were separated. The aqueous layer was extracted twice more and the organic layers were combined, dried (MgSO), and concentrated in vacuo. The crude complex was dissolved in acetone (1.6 mL) and water (0.27 mL) was added. The reaction was cooled with an ice bath and aqueous hydrogen bromide (0.27 mL) was added dropwise. The reaction was stirred at 0 ° C. Additional hydrogen bromide (0.27 mL) was added after 5 hours but no additional change was detected by thin layer chromatography. The acetone was removed in vacuo and a portion of methanol and three portions of ethanol were expelled. The crude was triturated first with ethanol and then with ether. Resulting two phases, and the lower one separated and washed with more ether, which was decanted. The remainder of the solvent was removed in vacuo. The yellow semi-solid was transferred using methanol and this was removed and expelled with two portions of ether. Providing 0.15 g; MS (ES +) 271 (MH +).
Examples 13 and 14 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide) Prepared as free base by a method analogous to that described in the Example 1 from dihydrochloride (S) -1-azabicyclo [2.2.2] oct-3-ylamine and trans-2-phenylcyclopropane-1-carboxylic acid. The diastereomers may be separated by chromatography on silica gel using a gradient of methanol / chloroform / 10-30% ammonium hydroxide; both MS (ES +) 271 (MH +).
Examples 15 and 16 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide) Prepared as free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and trans-2-phenylcyclopropane-1-carboxylic acid. The diastereomers may be separated by chromatography on silica gel using a gradient of methanol / chloroform / 10-30% ammonium hydroxide; both MS (ES +) 271 (MH +).
Example 17 (R) -N- (l-Azabicyclo [2. 2. 2] oct-3-yl) (-2-fluoro-3-phenylpropenamide) Prepared as a free base by a method analogous to that described in the Example 1 from dihydrochloride (R) -1-azabicyclo [2.2.2] oct-3-ylamine and Z-2-fluoro-3-phenylpropenoic acid; MS (ES +) 275 (MH +).
Example 18 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (2-formamidophenyl) -propenamide] Formic acid (98%, 2.9 mL) and acetic anhydride were combined. (1.0 mL) under an inert atmosphere while it is cooled with a bath of ice water. (R) -N- (l-azabicyclo [2.2.2] oct-3-yl) (E-3- (2-aminophenyl) propenamide) (0.16 g, 0.00059 mol) was added and the reaction was stirred for three days at room temperature. The solution was poured into saturated sodium carbonate and more solid carbonate was added until the solution was basic. The aqueous layer was extracted four times with chloroform. The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. The product was transferred using chloroform and this was removed and expelled with two portions of ether. The white solid was dried at room temperature under high vacuum, yielding 64 mg; MS (ES +) 300 (MH +).
Example 19 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-nitrophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (4-nitrophenyl) propenoic acid; MS (ES +) 302 (MH +).
Example 20 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-aminophenyl) -propenamide] Prepared by a method analogous to Example 9 from (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) [-3- (4-nitrophenyl) -propenamide); MS (ES +) 272 (MH +).
Example 21 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-formamidophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 18 (?) -N- (1-azabicyclo [2.2.2] oct-3-yl) (-3- (4-aminophenyl) propenamide); EM (ES +) 300 (MH +).
Example 22 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-methyl-3-phenylpropenamide) (A) 3-Methyl-3-phenylpropenoic acid Iodide was suspended from copper (I) (1.1 g, 0.006 mol) in anhydrous ether (20 mL) and the resulting suspension was kept at -10 ° C and shaken protected from light while slowly adding a commercial solution of methyl lithium l.OM (6 mL). The white suspension was stirred at -10 ° C for 30 minutes while the solid dissolved. 3-Phenylpropinoic acid (0.44 g, 0.003 mol) was added in three portions at -60 ° C. The reaction mixture was then stirred at -10 ° C for 90 minutes and then poured into dilute aqueous hydrochloric acid. Chloroform was added and the resulting emulsion was filtered through diatomaceous earth, and the phases were then separated. The aqueous layer was extracted three more times with chloroform. The organic layers were combined, dried (MgSO), and concentrated. The crude product was dried under high vacuum and used without further purification.
(B) (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-phenylpropenamide) Prepared as a free base by a method analogous to that described in the Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and i? -3-methyl-3-phenylpropenoic acid; MS (ES +) 271 (MH +).
Example 23 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-N-methylamino-phenyl) propenamide] Sodium metal (0.1 g, 0.0043 moles) was added ) in two portions to dry methanol (2 mL) was stirred at 0 ° C under nitrogen. After 20 minutes, (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) [-3- (4-aminophenyl) propenamide] (0.27 g, 0.001 mole) in methanol was added. for formaldehyde (0.18 g, 0.0006 moles), and the resulting solution was stirred at room temperature overnight. The reaction was heated at 50 ° C for 4 hours then sodium borohydride (0.10 g, 0.0028 mol) was added and the solution was heated under reflux for 2 hours. The reaction mixture was allowed to cool and aqueous potassium hydroxide (1 M, 0.8 mL) was added. After the resulting mixture had been stirred at room temperature for 1 hour, the solution was concentrated in vacuo, and the residue was partitioned between water and chloroform. The aqueous layer was extracted three more times with chloroform. The organic layers were combined, dried (MgSO4), and concentrated in vacuo. The material was first purified by solid phase extraction on silica using an ammoniated methanol / chloroform gradient of 10-40%, and then by reverse phase HPLC on a Waters Bondapak®C ?8 column using a 10-60 acetonitrile gradient. % and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was recovered by neutralization and extraction, yielding 45 mg of a yellow powder; MS (ES +) 286 (MH +).
Example 24 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (4-N ^ N-dimethylamino-phenyl) propenamide] Sodium cyanoborohydride (0.19 g) was combined , 0.003 mol) and anhydrous zinc chloride (0.21 g, 0.0015 mol) in anhydrous methanol. The mixture was stirred for 5 minutes and (R) -N- (1-azabicyclo [2.2.2] oct-3-yl) [-3- (4-a-inophenyl) propenamide] (0.27 g, 0.001 mole) was added. ) was dissolved in methanol (3 mL), followed by paraformaldehyde (0.18 g, 0.006 moles). The reaction mixture was stirred at room temperature overnight. The methanol was concentrated in vacuo and the residue was taken up in 1 M sodium hydroxide (20 mL). The aqueous layer was extracted three times with chloroform and these layers were combined, dried (MgSO4) and evaporated in vacuo. The material was first purified by solid phase extraction using gradient of 10-40% ammoniated methanol / chloroform, and then by reverse phase CIAR on a Waters BondapakOCia column using a gradient of 10-60% acetonitrile and aqueous trifluoroacetic acid at 1% as the eluent. The free base was recovered by neutralization and extraction, yielding 12 mg of yellow powder; MS (ES +) 300 (MH +).
Example 25 (aR) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (Z-3-phenylpropenamide) (A) i? -3-phenylpropenoic acid Tetrahydrate acetate nickel (II) was dissolved (0.16 g, 0.00063 mol) in ethanol (6.3 L) and placed under a hydrogen atmosphere. The green solution was stirred rapidly while sodium borohydride (0.024 g, 0.00063 mol) in ethanol (0.63 mL) was added. The deep purple solution was then treated with ethylene diamine (0.42 mL, 0.0063 mol) followed by 3-phenylpropionic acid (0.73 g, 0.005 mol). The reaction was stirred under hydrogen for 5 hours. Hydrogen was displaced with nitrogen and the suspension was filtered through diatomaceous earth to remove the catalyst. The filtrate was concentrated in vacuo. The residue was recovered in chloroform and water, and hydrochloric acid was added to acidify the aqueous layer. The layers were separated and the acidic layer was extracted three more times with chloroform. The organic layers were combined and concentrated. The material was purified by reverse phase HPLC on a Waters Bondapak®Ca column using a gradient of 10-40% acetonitrile and 0.25% aqueous trifluoroacetic acid as the eluent to give a white solid (0.51 g).
(B) (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (Z-3-phenylpropenamide) Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and Z-3-phenylpropenoic acid; MS (ES +) 257 (MH +).
Example 26 (R) -N- (1-Azabicyclo [2 .2.2] oct-3-yl) (3-methyl-3-phenyl-propenamide) (A) 3-methyl-3-phenylpropenoic acid A copper (I) bromide complex (1.72 g, 0.12 mol) and lithium bromide (1.0 g, 0.012 mol) was prepared in anhydrous tetrahydrofuran and cooled to -50 ° C. Commercial methyl magnesium bromide (3.0 M in ether, 4 mL) was added dropwise. The suspension was stirred at -50 ° C for 15 minutes, then 3-phenylpropionic acid (0.44 g, 0.003 mole) was added in three portions. The mixture was stirred at -50 ° C for 15 minutes and then directly heated at 30 ° C with a hot water bath. After stirring for one hour the reaction mixture was poured into saturated ammonium chloride. The solution was acidified by slow addition of concentrated hydrochloric acid and then extracted four times with chloroform. The organic layers were combined, dried (MgSO 4), and concentrated in vacuo. The material was purified by reverse phase HPLC on a Waters BandapakOCis column using a gradient of 20-60% acetonitrile and 0.25% aqueous trifluoroacetic acid as the eluent to give a colorless solid (0.14 g).
(B) (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-methyl-3-phenyl-propenamide) Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3-methyl-3-phenylpropenoic acid, giving a lightly tanned solid; EM (ES +) 271 (MH +).
Example 27 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (£ -2,3-diphenylpropenamide) Prepared as a free base by a method analogous to that described in Example 1 starting of (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -2,3-diphenylpropenoic acid; MS (ES +) 333 (MH +).
Example 28 (aR) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-methoxyphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-methoxy) phenylpropenoic acid hydrochloride; MS (ES +) 287 (MH +).
Example 29 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (2-methyl-3-phenyl-propenamide) Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -2-methyl-3-phenylpropenoic acid hydrochloride; MS (ES +) 271 (MH +).
Example 30 (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (2-methyl-3-phenyl-propenamide) Prepared as a free base by a method analogous to that described in Example 1 from (S) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and e-methyl-3-phenylpropenoic acid; MS (ES +) 271 (MH +).
Example 31 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-methylphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-methylphenyl) propenoic acid; MS (ES +) 271 (MH +).
Example 32 (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-methylphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (S) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-methylphenyl) propenoic acid hydrochloride; MS (ES +) 271 (MH +).
Example 33 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ - (2-methoxyphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-methoxyphenyl) propenoic acid; MS (ES +) 287 (MH +).
Example 34 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-methoxyphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (3-methoxyphenyl) -penoenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 287 (MH +).
Example 35 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (4-methoxyphenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-methoxyphenyl) propenoic acid; MS (ES +) 287 (MH +).
Example 36 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-fluorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-fluorophenyl) propenoic acid dihydrochloride; MS (ES +) 275 (MH +).
Example 37 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-fluorophenyl) -propenamide] Prepared by a method analogous to that described in Example 1 from of (R) -l-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (3-fluorophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 275 (MHT).
E 38 (R) -N- (l-Azabicyclo [2 .2 .2] oct-3-yl) [£ -3- (4-fluorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-fluorophenyl) -penoenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 275 (MH +).
Example 39 (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) [£ -3- (2-chlorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-chlorophenyl) propenoic acid; MS (ES +) 291 and 293 (MH +).
Example 40 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-chlorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (S) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-chlorophenyl) propenoic acid; MS (ES +) 291 and 293 (MH +).
Example 41 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-chlorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (3-chlorophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 291, 293 (MH +).
Example 42 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-chlorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-chlorophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 291, 293 (MH +).
Example 43 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-4-chlorophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (3-4-chlorophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 325, 327, 329 (MH +).
Example 44 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-bromophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (3-bromophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 335, 337 (MH +).
Example 45 (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-bromophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -l-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-bromophenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 335, 337 (MH +).
Example 46 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-iodophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (3-iodophenyl) propenoic acid; MS (ES +) 357 (MH +).
Example 47 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-iodophenyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (4-iodophenyl) propenoic acid; MS (ES +) 357 (MH +).
Example 48 (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (2-trifluoromethyl-phenyl) propenamide] Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-trifluoromethylphenyl) propenoic acid; MS (ES +) 325 (MH +).
Example 49 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3-trifluoromethyl-phenyl) propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (3-trifluoromethylphenyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 271 (MH +).
Example 50 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide] Prepared as a free base by a method analogous to that described in the Example 1 from (R) -l-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-furyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 247 (MH +).
Example 51 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (3-furyl) propenamide] Prepared as a free base by a method analogous to that described in the Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (3-furyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 247 (MH +).
Example 52 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-pyridyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (2-pyridyl) propenoic acid hydrochloride; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 258 (MH +).
Example 53 (R) -N- (l-Azabicyclo [2 .2,2] oct-3-yl) [-3- (3-pyridyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -l-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (3-pyridyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 258 (MHT).
Example 54 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-pyridyl) -propenamide] Prepared by a method analogous to that described in Example 1 from of (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (3-pyridyl) propenoic acid. The compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent. The product was dissolved in methanol, excess hydrogen chloride was added (1 M in ether). The solution was then evaporated, and recrystallization from methanol / t-butyl methyl ether gave the dihydrochloride salt of the title compound as a colorless solid; MS (ES +) 258 (MH +).
Example 55 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 starting from dihydrochloride (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (2-thienyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 263 (MH +).
Example 56 (-R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) -propenamide] Prepared by a method analogous to that described in Example 1 a starting from (R) -1-azabicyclo [2.2.2] oct-3-ylamine and -3- (3-thienyl) propenoic acid hydrochloride; the compound was purified by reverse phase HPLC on a Waters Bondapak® C? 8 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The solvent was evaporated from the fractions containing product, then the product was dissolved in aqueous hydrochloric acid and the solution was evaporated again giving the dihydrochloride salt of the title compound as a colorless solid; MS (ES +) 282 (MH +).
Example 57 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 starting with dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (5-nitro-2-furyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 293 (MH +).
Example 58 (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) [£ -3- (5-methoxy-3-pyridyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from (R) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and £ -3- (5-methoxy-3-pyridyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 288 (MH +).
Example 59 (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide] Prepared as a free base by a method analogous to that described in Example 1 starting with dihydrochloride of (R) -1-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (5-hydroxy-3-pyridyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 274 (MH +).
Example 60 (R) -N- (l-Azabicyclo [2 .2.2] oct-3-yl) [-3- (4-imidazolyl) -propenamide] Prepared as a free base by a method analogous to that described in Example 1 from dihydrochloride (R) -l-azabicyclo [2.2.2] oct-3-ylamine and £ -3- (4-.imidazolyl) propenoic acid; the compound was purified by chromatography on silica gel using mixtures of ammoniated methanol / chloroform as the eluent; MS (ES +) 247 (MH +).
Example 61 N- (endo-8-aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide) A mixture of 3a-aminopropane dihydrochloride (3.6 g), E-phenylpropenoic acid ( 2.5 g), l- [3- (dimethylamino) propyl] -3-ethyl-carbodihydrochloride; Lmida (3.2 g), and triethylamine (12 mL) in N, N-dimethylformamide (30 mL) was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The solution was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapak® C? 8 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloride salt was prepared by evaporating the fractions containing product, dissolving the residue in methanol, adding excess hydrogen chloride solution (1 M in diethyl ether) and evaporating. After drying under vacuum, the dihydrochloride salt of the title compound was obtained as a colorless solid (236 mg); MS (ES +) 307 (MH +).
Example 62 N- (Exo-8-aza-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide) A mixture of 3-aminotropane dihydrochloride (1.83 g), £ -3-phenylpropenoic acid (1.57 mg), 1-hydroxybenzotriazole hydrate (1.16 g), O-benzotriazole-1-yl-NrN tetrafluoroborate, N ', N /' - tetramethyluronium (2.76 g) , and?,? -diisopropylethylamine (6.0 mL) in?,? -dimethylformamide (15 mL) was stirred at room temperature overnight. The solution was evaporated, and the residue was partitioned between aqueous sodium hydroxide and chloroform. The solution was evaporated and the residue was purified by reverse phase HPLC on a Waters Bondapal® C? 8 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The hydrochloride salt was prepared by evaporation of the fractions containing product, dissolution of the residue in methanol, addition of excess hydrogen chloride solution (1 M in diethyl ether) and evaporation. After drying under vacuum, the dihydrochloride salt of the title compound was obtained as a colorless solid (243 mg); MS (ES +) 307 (MHT).
Example 63 (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (2-furyl) propenamide) Prepared as a free base by a method analogous to that described in the Example 1 from (S) -1-azabicyclo [2.2.2] oct-3-ylamine dihydrochloride and E-3- (2-furylpropenoic acid), the compound was purified by chromatography on silica gel using ammoniated methanol mixtures. chloroform as the eluent, followed by recrystallization from ethyl acetate / hexane; MS (ES +) 247 (MH +).
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (42)

  1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of a compound of the general formula I where: A represents: D represents oxygen, or sulfur; R1 represents hydrogen or methyl; R 2 represents hydrogen, or C 1 -C 4 alkyl; R3 represents: R4, R5 and R6 are independently hydrogen, halogen, C? -C4 alkyl, C2-C4 alkenyl, C? -C alkynyl, -C02R7, -CN, -CF, or Ar, provided that at least one of R4 and R5 represent Ar; Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, or a fused heteroaromatic or aromatic ring system of 8, 9 or 10 elements containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may be optionally substituted with one or more substituents selected from the following: hydrogen, halogen, C? -C4 alkyl , C2-C4 alkenyl, C2-C4 alkynyl, aryl, heteroaryl, -C02R7, -CN, -N02, -NR8R9, -CF3, -OR10; R8, R9, and R10 are independently hydrogen, C? -C4 alkyl, aryl, heteroaryl, -C (0) Rn, -C (0) NHR12, -C (0) R13, -S02R14 or R8 and R9 can together be (CH2) Q (CH2) k where Q is O, S, NR15, or a bond: j is 2 to 4; k is 0 to 2; R 7, R 10, R 11, R 12, R 13, R 14 and R 15 are independently C 1 -C 4 alkyl, aryl, or heteroaryl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof, are employed for the preparation of a medicament for the treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration. 2. The use according to claim 1, wherein: A represents: II 3. The use according to claim 1 or claim 2, wherein D represents oxygen. 4. The use according to any of claims 1 to 3, wherein R2 represents hydrogen. 5. The use according to any of claims 1 to 4, wherein R3 represents 6. The use according to any of claims 1 to 4, wherein R3 represents R4 represents Ar; R5 represents hydrogen, or C? -C4 alkyl; R6 represents hydrogen, or halogen. 7. The use according to claim 1, wherein: A represents II D represents oxygen; R2 represents hydrogen; and R represents: 8. The use according to claim 1, wherein the compound of formula I is a compound wherein: A represents II D represents oxygen; R represents hydrogen; R represents R4 represents .Ar; R5 represents hydrogen, or d-C4 alkyl; and R6 represents hydrogen, or halogen. 9. The use according to any one of claims 1 to 8, wherein Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom , or a fused heteroaromatic or aromatic ring system of 8, 9 or 10 elements containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may be optionally substituted with one or more than substituents selected from the following: hydrogen, halogen, C? -C alkyl, C2-C4 alkenyl, C2-C alkynyl, aryl, heteroaryl, -C02R7, -CN, -N02, -NR8R -CF3, and -OR1 10. The use according to claim 1, wherein said compound is: N- (1-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); N- (1-Azabicyclo) [2.2.2] oct-3-yl) (3-phenylpropionamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) propenamide]; N- ( l-Azabicyclo [2.2 .2] oct-3-yl) [-3- (2-nitrophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [1 -3- (2-aminophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [Z -3- (2-methoxyphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) -N-methyl- (£ -3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [2-phenylcyclopropane-1-carboxamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-2-fluoro-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-phenyl-phenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-nitrophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -3- (4-aminophenyl) propenamide; N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -3 - (4-fo ^ paamidophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) (2-3-methyl-3-phenylpropenamide) N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-N-methylaminophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-N, N- dimethylaminophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) (Z-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-methyl-3-phenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) (-2-, 3-diphenylpropenamide); N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-methoxyphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-methyl-3-phenylpropenamide); N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-methylphenyl) propenamide]; AT- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-methoxyphenyl) ropenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-fluorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [1 -3- (4-fluorophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-chlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-chlorophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-chlorophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3,4-dichlorophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3-bromo phenyl) propenamide]; ? - (1-Azabicyclo [2.2.2] oct-3-yl) - [-3- (4-bromophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-iodophenyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-iodophenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-trifluoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) - [1 -3- (3-trifluoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide]; N- (1-Azabicyl, or [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; N- (1-Azabicyclo [2 .2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-methoxy-3-pyridyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; N- (endo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide); N- (exo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide); or an enantiomer thereof, and pharmaceutically acceptable salts thereof. The use according to claim 1, wherein said compound is: (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3-phenylpropenamide); (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropinamide); (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (3-phenylpropinamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-nitrophenyl) ropenamide]; (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-aminophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-aminophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [Z-3- (2-methoxyphenyl) propenamide]; (RS) -N- (1-Azabicyclo [2.2.2] oct-3-yl) -N-methyl- (3-phenylpropenamide); (S) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide); (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (2-phenylcyclopropane-1-carboxamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-formamidephenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-nitrophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3- (4-aminophenyl) propenamide; (R) -N- (l-Azabicyclo [2.2.2] oct- 3-yl) (-3- (4-phenyl) -amidephenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-N-methylaminophenyl) propenamide]; (i?) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (4-N? N -di- ethylaminophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (Z-3-phenylpropenamide); (R) -N- (1-Azabicyclo [2.2.2] oct-3-yl) (3-methyl-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -2,3-diphenylpropenamide); . (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (-3- (4-methoxyphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct -3-yl) (£ -2-methyl-3-phenylpropenamide); (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) (£ -2-methyl-3-phenylpropenamide); (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ -3- (2-methylphenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct -3-yl) [-3- (2-methylphenyl) propenamide]; (? S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-ethoxyphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-methoxyphenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-methoxyphenyl) propenamide]; (RS) -N- (1-Azabicyclo [2 .2.2] oct-3-yl) [-3- (2-fluorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-fluorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-fluorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-chlorophenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E - (2-chlorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-chlorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-chlorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3,4-dichlorophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (3-bromophenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [-3- (4-bromophenyl) propenamide]; (RS) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-iodophenyl) propenamide]; (S) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-iodophenyl) propenamide]; (RS) -N- (l-.Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-trifluoromethylphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) - [E-3- (3-trifluoromethylphenyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (2-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-7-3- (2-thienyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-methoxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; N- (endo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide); N- (exo-8-Aza-8-methylbicyclo [3.2.1] oct-3-yl) (-3-phenylpropenamide), or an enantiomer thereof, and pharmaceutically acceptable salts thereof. 12. A compound of the general formula I where: A represents: II III IV V VI D represents oxygen, or sulfur; R1 represents hydrogen or methyl; R 2 represents hydrogen, or C 1 -C 4 alkyl; R3 represents: R4, R5 and R6 are independently hydrogen, halogen, C?-C4 alkyl / C2-C4 alkenyl, C2-C4 alkynyl, -C02R7, -CN, -CF3, or Ar, provided that at least one of R4 and R5 represent Ar; Ar represents a 5- or 6-membered heteroaromatic or aromatic ring containing zero to three nitrogen atoms, zero or one oxygen atom, and zero or one sulfur atom, or a fused heteroaromatic or aromatic ring system of 8, 9 or 10 elements containing zero to four nitrogen atoms, zero to one oxygen atom, and zero to one sulfur atom which may be optionally substituted with one or more substituents selected from the following: hydrogen, halogen, C? -C4 alkyl , C2-C alkenyl, C2-C4 alkynyl / aryl, heteroaryl, -C02R7, -CN, -N02, -NR8RP, -CF5, - R 8, R 9, and R 10 are independently hydrogen, C 1 -C 4 alkyl, aryl, heteroaryl, -C (0) R, -C (0) NHR, -C (0) R 13, -S02R 14 or R 8 and R 9 can together be (CH2) jQ (CH2) k where Q is O, S, NR15, or a bond: j is 2 to 4; k is 0 to 2; R7, R10, R11, R12, R13, R14 and R15 are independently C?-C4 alkyl / aryl, or heteroaryl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof, with the proviso that Ar does not represent 2-, 3-, 4-pyridyl, unsubstituted phenyl or substituted phenyl with one or more substituents selected from C? -C alkyl , C 1 -C 4 alkoxy, halogen, phenoxy, hydroxy, OCOR 11, NH 2, NHCOR 11, and nitro, when: A represents II VI R represents D represents oxygen; R represents methyl; R2 and R5 both represent hydrogen; and R6 represents any of hydrogen, C? -C4 alkyl, phenyl, or cyano. 13. A compound according to claim 12, wherein A represents: II or an enantiomer thereof, and pharmaceutically acceptable salts thereof. 14. A compound according to claim 13, characterized in that Rd represents any of 2-furyl; 3-furyl; 2-thienyl; 3-thienyl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. 15. A compound according to claim 12, characterized in that the compound is: N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ 7-3- (3-trifluoromethylphenyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (2-thienyl) propenamide]; N- (1-α-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; N- (1-Aza-3-cyanobicyclo [2.2.2] oct-3-yl) [3-phenyl-ro enamide]; N- (1-Aza-3-methylbicyclo [2.2.2] oct-3-yl) [£ 7-3-phenylpropenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [£ -3 ~ (5-nitro-2-furyl) propenamide]; N- (1-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-methoxy-3-pyridyl) propenamide]; N- (l-Azab? Cycle [2.2.2] oct-3-yl) [£ -3- (5-hydroxy-3-pyridyl) propenamide]; N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-.imidazolyl) propenamide]; or an enantiomer and / or pharmaceutically acceptable salts thereof. 16. A compound according to claim 12, characterized in that said compound is: (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ 7-3- (3-trifluoromethylphenyl) ropenamide ]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ 7-3- (2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [£ 7-3- (2-thienyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (3-thienyl) propenamide]; N- (l-Aza-3-cyanobicyclo [2.2.2] oct-3-yl) [£ 7-3-phenylpropenamide]; N- (l-Aza-3-methylbicyclo [2.2.2] oct-3-yl) [E-3-phenylpropenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-nitro-2-furyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (5-methoxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [-3- (5-hydroxy-3-pyridyl) propenamide]; (R) -N- (l-Azabicyclo [2.2.2] oct-3-yl) [E-3- (4-imidazolyl) propenamide]; or an enantiomer thereof, and pharmaceutically acceptable salts thereof. 17. A compound according to any of claims 12 to 16, for use in therapy. 18. The use of a compound as defined in any of claims 12 to 16, in the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration. 19. The use of a compound as defined in any of claims 12 to 16, in the manufacture of a medicament for the treatment or prophylaxis of human conditions or conditions in which activation of the nicotinic acetylcholine receptor oc7 is beneficial. 20. The use of a compound according to any of claims 12 to 16 in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficiency, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Lewy Body Dementia, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is cholinergic synapse loss, jetlag, smoking cessation , nicotinic addition including that resulting from exposure to products containing nicotine, pain, and ulcerative colitis. The use according to claim 20, wherein the condition or disorder is Alzheimer's disease, learning deficiency, cognition deficiency, attention deficit, memory loss, Lewy Body Dementia or Deficit Hyperactivity Disorder of Attention. 22. The use according to claim 20, wherein the disorder is anxiety, schizophrenia or mania or manic depression. 23. The use according to claim 20, wherein the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is a loss of the cholinergic synapse. 24. The use according to claim 20, wherein the condition or disorder is jetlag, nicotinic addiction including that resulting from exposure to products containing nicotine, pain or ulcerative colitis. 25. The use according to claim 20, wherein the condition or disorder is Alzheimer's disease. 26. A pharmaceutical composition characterized in that it includes a compound according to any of claims 12 or 16, in admixture with a pharmaceutically acceptable inert diluent or carrier. 27. The pharmaceutical composition according to claim 26, for use in the treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration. 28. The pharmaceutical composition according to claim 26, for use in the treatment or prophylaxis of human conditions or conditions in which activation of the nicotinic receptor a.7 is beneficial. 29. The pharmaceutical composition of claim 26, for use in the treatment or prophylaxis of Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficiency, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia , mania or manic depression, Lewy Body Dementia, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is cholinergic synapse loss, jetlag, cessation of smoking, nicotinic addition including that resulting from exposure to products that contain nicotine, pain, and ulcerative colitis. 30. The pharmaceutical composition according to claim 29, for use in the treatment or prophylaxis of Alzheimer's disease, learning deficiency, cognition deficiency, attention deficit, memory loss, Lewy Body Dementia or Hyperactivity Disorder. Deficiency of Attention. The pharmaceutical composition according to claim 29, for use in the treatment or prophylaxis of anxiety, schizophrenia or mania or manic depression. 32. The pharmaceutical composition according to claim 29, for use in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is a loss of the cholinergic synapse. 33. The pharmaceutical composition according to claim 29, for use in the treatment or prophylaxis of jetlag, nicotinic addiction including that resulting from exposure to products containing nicotine, pain or ulcerative colitis. 34. The pharmaceutical composition according to claim 29, for use in the treatment or prophylaxis of Alzheimer's disease. 35. A method of treatment or prophylaxis of psychotic disorders or disorders of intellectual deterioration, characterized in that it includes a therapeutically effective amount of a compound as defined in any of claims 12 to 16. 36. A method of treatment or prophylaxis of conditions or human conditions, in which the activation of nicotinic receptor a7 is beneficial, characterized in that it comprises administering a therapeutically effective amount of a compound as defined in any of claims 12 to 16. 37. The method of claim 35 or 36, characterized in that the disorder is Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Dementia Lewy Body, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotinic addition including that resulting from exposure to products containing nicotine, pain, and ulcerative colitis. 38. The method according to claim 37, characterized in that the disorder is Alzheimer's disease, learning deficiency, deficiency of cognition, attention deficiency, memory loss, Lewy Body Dementia or Hyperactivity Disorder of Deficiency of the Attention. 39. The method according to claim. 37, characterized in that the disorder is Parkinson's disease, Huntington's disease, Tourette's syndrome, or neurodegenerative disorders in which there is a loss of the cholinergic synapse. 40. The method according to claim 37, characterized in that the disorder is anxiety, schizophrenia or mania or manic depression. 41. The method according to claim 37, characterized in that the disorder is jetlag, nicotinic addiction, pain and ulcerative colitis. 42. The method according to claim 37, characterized in that the disorder is the Alzheimer's disease.
MXPA02004911A 1999-11-18 2000-11-16 New use and novel n azabicyclo amide derivatives. MXPA02004911A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9904176A SE9904176D0 (en) 1999-11-18 1999-11-18 New use
PCT/SE2000/002262 WO2001036417A1 (en) 1999-11-18 2000-11-16 New use and novel n-azabicyclo-amide derivatives

Publications (1)

Publication Number Publication Date
MXPA02004911A true MXPA02004911A (en) 2002-09-18

Family

ID=20417766

Family Applications (1)

Application Number Title Priority Date Filing Date
MXPA02004911A MXPA02004911A (en) 1999-11-18 2000-11-16 New use and novel n azabicyclo amide derivatives.

Country Status (31)

Country Link
US (1) US6683090B1 (en)
EP (1) EP1233964B1 (en)
JP (1) JP2003514818A (en)
KR (1) KR20020058014A (en)
CN (1) CN1217943C (en)
AR (1) AR031680A1 (en)
AT (1) ATE298337T1 (en)
AU (1) AU784400B2 (en)
BG (1) BG106680A (en)
BR (1) BR0015624A (en)
CA (1) CA2389604A1 (en)
CO (1) CO5261607A1 (en)
CZ (1) CZ20021692A3 (en)
DE (1) DE60020994T2 (en)
DK (1) DK1233964T3 (en)
EE (1) EE200200251A (en)
ES (1) ES2242653T3 (en)
HK (1) HK1047743A1 (en)
HU (1) HUP0204245A3 (en)
IL (1) IL149374A0 (en)
IS (1) IS6385A (en)
MX (1) MXPA02004911A (en)
NO (1) NO20022289L (en)
NZ (1) NZ518571A (en)
PL (1) PL355867A1 (en)
PT (1) PT1233964E (en)
SE (1) SE9904176D0 (en)
SK (1) SK6772002A3 (en)
UA (1) UA74172C2 (en)
WO (1) WO2001036417A1 (en)
ZA (1) ZA200203316B (en)

Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
SE0000540D0 (en) 2000-02-18 2000-02-18 Astrazeneca Ab New compounds
US6479510B2 (en) 2000-08-18 2002-11-12 Pharmacia & Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
US6492385B2 (en) 2000-08-18 2002-12-10 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
AU2001284645A1 (en) * 2000-08-18 2002-03-04 Pharmacia And Upjohn Company Quinuclidine-substituted aryl compounds for treatment of disease
WO2002016357A2 (en) * 2000-08-18 2002-02-28 Pharmacia & Upjohn Company Quinuclidine-substituted aryl moieties for treatment of disease (nicotinic acetylcholine receptor ligands)
AU2001284646A1 (en) * 2000-08-21 2002-03-04 Pharmacia And Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
EP1311505A2 (en) * 2000-08-21 2003-05-21 PHARMACIA &amp; UPJOHN COMPANY Quinuclidine-substituted heteroaryl moieties for treatment of disease ( nicotinic acetylcholine receptor ligands )
US6500840B2 (en) 2000-08-21 2002-12-31 Pharmacia & Upjohn Company Quinuclidine-substituted heteroaryl moieties for treatment of disease
PE20021019A1 (en) 2001-04-19 2002-11-13 Upjohn Co SUBSTITUTED AZABYCLE GROUPS
AR036041A1 (en) * 2001-06-12 2004-08-04 Upjohn Co HETEROCICLIC AROMATIC COMPOUNDS REPLACED WITH QUINUCLIDINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
AR036040A1 (en) 2001-06-12 2004-08-04 Upjohn Co MULTICICLIC HETEROARYL COMPOUNDS REPLACED WITH QUINUCLIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
DK1406900T3 (en) 2001-07-06 2007-01-29 Neurosearch As New compounds, preparation and use thereof
BR0212101A (en) * 2001-08-24 2004-08-24 Pharmacia & Up John Company 7-aza [2.2.1] heteroaryl substituted bicycloheptanes for the treatment of disease
PL369895A1 (en) * 2001-10-02 2005-05-02 Pharmacia & Upjohn Company Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease
WO2003032897A2 (en) * 2001-10-16 2003-04-24 Astrazeneca Ab Azabicyclic compounds for the treatment of fibromyalgia syndrome
US6849620B2 (en) 2001-10-26 2005-02-01 Pfizer Inc N-(azabicyclo moieties)-substituted hetero-bicyclic aromatic compounds for the treatment of disease
CA2464194A1 (en) * 2001-10-26 2003-05-08 Pharmacia & Upjohn Company N-azabicyclo-substituted hetero-bicyclic carboxamides as nachr agonists
EP1442041A1 (en) 2001-11-08 2004-08-04 PHARMACIA &amp; UPJOHN COMPANY Azabicyclic-substituted-heteroaryl compounds for the treatment of disease
CA2466344A1 (en) 2001-11-09 2003-05-22 Pharmacia & Upjohn Company Azabicyclic-phenyl-fused-heterocyclic compounds and their use as alpha7 nachr ligands
CN100371714C (en) 2001-12-14 2008-02-27 塔加西普特公司 Methods and compositions for treatment of central nervous system disorders
DE10164139A1 (en) 2001-12-27 2003-07-10 Bayer Ag 2-heteroaryl carboxamides
EP1480977A2 (en) 2002-02-15 2004-12-01 PHARMACIA &amp; UPJOHN COMPANY Substituted aryl compounds for treatment of disease
WO2003070731A2 (en) 2002-02-19 2003-08-28 Pharmacia & Upjohn Company Azabicyclic compounds for the treatment of disease
AU2003219690A1 (en) * 2002-02-19 2003-09-09 Pharmacia And Upjohn Company Fused bicyclic-n-bridged-heteroaromatic carboxamides for the treatment of disease
CN1656093A (en) 2002-05-30 2005-08-17 神经研究公司 3-substituted quinuclidines and their use
AU2003253686A1 (en) 2002-08-01 2004-02-23 Pharmacia & Upjohn Company Llc 1h-pyrazole and 1h-pyrrole-azabicyclic compounds with alfa-7 nachr activity
EP2298759A1 (en) 2002-08-30 2011-03-23 Memory Pharmaceuticals Corporation Anabaseine derivatives useful in the treatment of neurodegenerative diseases
GB0220581D0 (en) 2002-09-04 2002-10-09 Novartis Ag Organic Compound
CZ2005252A3 (en) 2002-09-25 2005-11-16 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles and benzoisothiazoles, their preparation and use
AU2003279492A1 (en) * 2002-12-11 2004-06-30 Pharmacia & Upjohn Company Llc Treatment of diseases with combinations of alpha 7 nicotinic acetylcholine receptor agonists and other compounds
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
EP1735306A2 (en) 2004-03-25 2006-12-27 Memory Pharmaceuticals Corporation Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof
PE20060437A1 (en) 2004-06-18 2006-06-08 Novartis Ag AZA-BICYCLONONE COMPOUNDS AS CHOLINERGIC LINKS OF nAChR
GB0415746D0 (en) 2004-07-14 2004-08-18 Novartis Ag Organic compounds
JP2009506037A (en) 2005-08-22 2009-02-12 ターガセプト，インコーポレイテッド Heteroaryl-substituted diazatricycloalkanes, methods for their preparation and methods for their use
JP5109132B2 (en) * 2005-09-28 2012-12-26 国立大学法人 熊本大学 Drugs for attention deficit / hyperactivity disorder
GB0521508D0 (en) 2005-10-21 2005-11-30 Novartis Ag Organic compounds
GB0525672D0 (en) 2005-12-16 2006-01-25 Novartis Ag Organic compounds
GB0525673D0 (en) 2005-12-16 2006-01-25 Novartis Ag Organic compounds
WO2008008884A2 (en) * 2006-07-12 2008-01-17 Cornell Research Foundation, Inc. Inhibition of beta-amyloid peptide aggregation
TW200901974A (en) 2007-01-16 2009-01-16 Wyeth Corp Compounds, compositions, and methods of making and using them
SA08290475B1 (en) 2007-08-02 2013-06-22 Targacept Inc (2S,3R)-N-(2-((3-Pyridinyl)Methyl)-1-Azabicyclo[2.2.2]Oct-3-yl)Benzofuran-2-Carboxamide, Novel Salt forms, and Methods of Use Thereof
CN104193741B (en) 2007-10-01 2016-08-24 阿尔法梅根有限责任公司 Quinuclidine-4-ylmethyl 1H-indole-3-carboxylic acid ester derivant as alpha 7 nicotinic acetylcholine receptor ligands
PT2254598E (en) 2008-02-13 2013-10-16 Targacept Inc Combination of alpha 7 nicotinic agonists and antipsychotics
TW201031664A (en) 2009-01-26 2010-09-01 Targacept Inc Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide
MX2012013345A (en) 2010-05-17 2013-02-11 Envivo Pharmaceuticals Inc A crystalline form of (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]th iophene-2-carboxamide hydrochloride monohydrate.
FR2974365B1 (en) * 2011-04-20 2017-08-25 Centre Nat De La Rech Scient (C N R S) 1,4-DISUBSTITUTED 1,2,3-TRIAZOLES, METHODS FOR PREPARING THEM AND DIAGNOSTIC AND THERAPEUTIC USES THEREOF
WO2012177856A2 (en) * 2011-06-21 2012-12-27 Adispell, Inc. Cognition modification
GB201111704D0 (en) 2011-07-07 2011-08-24 Takeda Pharmaceutical Novel compounds
GB201111705D0 (en) 2011-07-07 2011-08-24 Takeda Pharmaceutical Compounds and their use
JO3115B1 (en) 2011-08-22 2017-09-20 Takeda Pharmaceuticals Co Pyridazinone Compounds and Their Use as DAAO Inhibitors
CA2872005A1 (en) 2012-05-08 2013-11-14 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
GB201209587D0 (en) 2012-05-30 2012-07-11 Takeda Pharmaceutical Therapeutic compounds
EP2953940B1 (en) 2013-02-07 2018-08-22 Heptares Therapeutics Limited Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic m4 receptor agonists
EA029430B1 (en) 2013-06-21 2018-03-30 Такеда Фармасьютикл Компани Лимитед 1-sulfonyl piperidine derivatives as modulators of prokineticin receptors
GB201314286D0 (en) 2013-08-08 2013-09-25 Takeda Pharmaceutical Therapeutic Compounds
GB201318222D0 (en) 2013-10-15 2013-11-27 Takeda Pharmaceutical Novel compounds
GB201320905D0 (en) 2013-11-27 2014-01-08 Takeda Pharmaceutical Therapeutic compounds
TW201613864A (en) 2014-02-20 2016-04-16 Takeda Pharmaceutical Novel compounds
US9434724B2 (en) 2014-07-11 2016-09-06 Alpharmagen, Llc Quinuclidines for modulating alpha 7 activity
US9724340B2 (en) 2015-07-31 2017-08-08 Attenua, Inc. Antitussive compositions and methods
GB201616839D0 (en) 2016-10-04 2016-11-16 Takeda Pharmaceutical Company Limited Therapeutic compounds
GB201619514D0 (en) 2016-11-18 2017-01-04 Takeda Pharmaceuticals Co Novel compounds
JP2021138648A (en) 2020-03-04 2021-09-16 武田薬品工業株式会社 Oral solid preparation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1255467B (en) * 1992-07-29 1995-11-02 Dompe Farmaceutici Spa PHARMACOLOGICALLY ACTIVE ACRYLIC STARCHES
GB9304500D0 (en) * 1993-03-05 1993-04-21 Glaxo Spa Heterocyclic compounds
CA2209936A1 (en) * 1995-01-10 1996-07-18 Smithkline Beecham S.P.A. Indole derivatives useful in the treatment of osteoporosis

Also Published As

Publication number Publication date
AR031680A1 (en) 2003-10-01
IS6385A (en) 2002-05-15
NO20022289D0 (en) 2002-05-14
WO2001036417A1 (en) 2001-05-25
NO20022289L (en) 2002-06-24
DK1233964T3 (en) 2005-09-19
CA2389604A1 (en) 2001-05-25
ZA200203316B (en) 2004-02-25
CO5261607A1 (en) 2003-03-31
SK6772002A3 (en) 2002-09-10
IL149374A0 (en) 2002-11-10
US6683090B1 (en) 2004-01-27
PT1233964E (en) 2005-09-30
HK1047743A1 (en) 2003-03-07
EE200200251A (en) 2003-06-16
ATE298337T1 (en) 2005-07-15
SE9904176D0 (en) 1999-11-18
CN1217943C (en) 2005-09-07
ES2242653T3 (en) 2005-11-16
JP2003514818A (en) 2003-04-22
AU784400B2 (en) 2006-03-23
HUP0204245A3 (en) 2004-12-28
KR20020058014A (en) 2002-07-12
BG106680A (en) 2003-01-31
NZ518571A (en) 2004-05-28
UA74172C2 (en) 2005-11-15
CN1423651A (en) 2003-06-11
AU1907301A (en) 2001-05-30
EP1233964B1 (en) 2005-06-22
DE60020994T2 (en) 2006-04-27
CZ20021692A3 (en) 2003-01-15
HUP0204245A2 (en) 2003-03-28
BR0015624A (en) 2002-07-30
PL355867A1 (en) 2004-05-31
EP1233964A1 (en) 2002-08-28
DE60020994D1 (en) 2005-07-28

Similar Documents

Publication Publication Date Title
MXPA02004911A (en) New use and novel n azabicyclo amide derivatives.
ES2316848T3 (en) BIARIL DIAZABICICLOALCANO AMIDAS AS AGONISTS OF NICOTINICS OF ACETILCOLINE.
AU782693B2 (en) Novel biarylcarboxamides
EP1539764B1 (en) Aryl-substituted diazabicycloalkanes as nicotinic acetylcholine agonists.
ES2204711T3 (en) QUINUCLIDINE ACRYLAMIDS.
EP1673372B1 (en) Non-amide nonanes

Legal Events

Date Code Title Description
FG Grant or registration